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Curaxin CBL0137 inhibits endothelial inflammation and atherogenesis via suppression of the Src‐YAP signalling axis

Authors :
Huanyu Ding
Minchun Jiang
Chi Wai Lau
Jianfang Luo
Andrew M. Chan
Li Wang
Yu Huang
Source :
British Journal of Pharmacology. 180:1168-1185
Publication Year :
2022
Publisher :
Wiley, 2022.

Abstract

Atherosclerotic vascular disease is the leading cause of mortality and morbidity worldwide. Our previous study uncovered that endothelium-specific knockdown of YAP suppresses atherogenesis, suggesting that YAP is a promising therapeutic target against atherosclerotic vascular disease. We established a drug screening platform, which aimed to identify new YAP inhibitors for anti-atherosclerotic treatment.Drug screening was performed by a luciferase reporter gene assay. RNA sequencing was performed to acquire the transcriptomic profile of CBL0137-treated endothelial cells. We assessed and validated the inhibitory effect of CBL0137 on YAP activity and inflammatory response in HUVECs and HAECs. We evaluated the vasoprotective effect of CBL0137 in vivo against plaque formation in ApoEWe identified CBL0137 as a novel YAP inhibitor from an FDA drug library. CBL0137 inhibited YAP activity by restraining its phosphorylation at Y357. CBL0137 inhibited YAP activity to repress endothelial inflammation. Mechanistically, CBL0137 suppressed YAP phosphorylation at Y357 via the tyrosine-protein kinase Src. Furthermore, administration of CBL0137 ameliorated endothelial inflammation and the atherogenesis induced by disturbed flow and consumption of an atherogenic diet in ApoETo our knowledge, this is the first study to identify CBL0137 as a novel YAP inhibitor. We have demonstrated that pharmacologically targeting YAP by CBL0137 inhibits atherogenesis. The present results suggest that CBL0137 holds promise as a new drug for the treatment of atherosclerotic vascular disease.

Subjects

Subjects :
Pharmacology

Details

ISSN :
14765381 and 00071188
Volume :
180
Database :
OpenAIRE
Journal :
British Journal of Pharmacology
Accession number :
edsair.doi.dedup.....40f4ae105f5151b3a8b1c3c9a721a412